FRAGMENT BASED DRUG DISCOVERY TARGETING HIV PROTEASE

该子项目是利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 研究中心，而研究中心不一定是研究者所在的机构。 IV型皮利（T4 P）是许多细菌病原体的关键毒力因子，介导广泛的功能，包括表面运动、小菌落形成、粘附、噬菌体附着和自然转化。IV型皮利具有很大的科学意义，因为这些丝状体在细菌发病机制中起着中心作用，并且它们具有作为抗菌干预靶点的潜力。此外，从生物物理学的角度来看，菌毛组装装置代表了一个显着的和独特的分子马达。我们正在努力解决IV型菌毛组装装置的内膜平台组件的晶体结构。这些数据将与从固态NMR，电子显微镜，突变分析和生物化学获得的结构数据相结合，以获得对这一关键分子机器的详细了解。这项工作可能有助于设计新的抗菌治疗方法，并有助于我们了解另一个关键的细菌毒力系统，即与IV型菌毛系统高度相似的2型分泌。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Type IV pili (T4P) are key virulence factors for many bacterial pathogens, mediating a broad range of functions including surface motility, microcolony formation, adhesion, phage attachment and natural transformation. Type IV pili are of great scientific interest due to the central role these filaments play in bacterial pathogenesis and for their potential as targets for antibacterial interventions. Furthermore, from a biophysical standpoint, the pilus assembly apparatus represents a remarkable and unique molecular motor. We are working to solve the crystal structures of the components of the inner membrane platform of the Type IV pilus assembly apparatus. These data will be combined with structural data obtained from solid state NMR, electron microscopy, mutational analysis and biochemistry to obtain a detailed understanding of this critical molecular machine. This work will likely contribute to the design of new antibacterial therapies and to our understanding of another critical bacterial virulence system, the Type 2 secretion, which is highly similar to Type IV pilus system.